Excessive and ectopic smooth muscle cells (SMCs) and smooth muscle-derived cells accumulate in diverse vascular diseases but underlying mechanisms are poorly understood. Seminal work from our lab as well as other labs indicate that SMC progenitors play a vital role in this process. In paradigm-shifting studies, we recently identified pools of SMC progenitors in the lung that we reasoned were primed to muscularize distal arterioles based on their location at the muscular- unmuscular border of each pulmonary arteriole and their molecular signature of expressing SMC markers and the undifferentiated mesenchyme marker platelet-derived growth factor receptor (PDGFR)-?. Upon exposing mice to hypoxia, expression of the ligand PDGF-B by lung endothelial cells and macrophages induces these primed cells to express the pluripotency factor Kruppel-like factor 4 (KLF4) and in each arteriole, one of them migrates distally and clonally expands. This pathological muscularization results in pulmonary hypertension. Similarly, in atherosclerosis of systemic arteries, our recent results indicate that a single or rare SMC marker+ cells gives rise to most of the cells in an advanced plaque, and the vast majority of these cells have been shown to express markers of macrophages, stem cells or undifferentiated mesenchyme but not SMCs. Remarkably, our findings demonstrate that bone marrow-derived cells (most likely macrophages) non-cell autonomously regulate the number of SMCs recruited into a plaque and suggest that the number of SMC progenitors recruited into a plaque dictates the progression of atherosclerosis. Thus, these novel SMC progenitors are critical to the pathogenesis of pulmonary hypertension and atherosclerosis, but little is known regarding their origin, development, gene expression, maintenance and the mechanisms underlying their role in disease pathogenesis. In this proposal, we will use mouse models, isolated murine cells, human tissue and myeloid cells isolated from humans. We will identify SMC progenitors in the aorta and meticulously characterize both these progenitors and those in the pulmonary arterioles. In addition, we will delineate progenitor cell origins and development as well as their role in morphogenesis of the tunica media. Mechanisms underlying their clonal expansion in disease and the non-cell autonomous regulation of progenitor cells will be investigated. Taken together, our research program promises to yield seminal insights into this novel progenitor cell type that is vitally important for vascular pathologies and thereby, provide therapeutic strategies for combatting lethal diseases of the vasculature, such as pulmonary hypertension and atherosclerosis.